Controlled human infection models to evaluate schistosomiasis and hookworm vaccines: where are we now?

Host-parasite interactio

Immunological considerations for schistosoma vaccine development: transitioning to endemic settings

Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.Host-parasite interactio

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings.

Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds

Risk assessment for the implementation of controlled human Schistosoma mansoni infection trials in Uganda.

Schistosomiasis is a parasitic infection highly prevalent in sub-Saharan Africa, and a significant cause of morbidity; it is a priority for vaccine development. A controlled human infection model for Schistosoma mansoni (CHI-S) with potential to accelerate vaccine development has been developed among naïve volunteers in the Netherlands. Because responses both to infections and candidate vaccines are likely to differ between endemic and non-endemic settings, we propose to establish a CHI-S in Uganda where Schistosoma mansoni is endemic. As part of a "road-map" to this goal, we have undertaken a risk assessment. We identified risks related to importing of laboratory vector snails and schistosome strains from the Netherlands to Uganda; exposure to natural infection in endemic settings concurrently with CHI-S studies, and unfamiliarity of the community with the nature, risks and rationale for CHI. Mitigating strategies are proposed. With careful implementation of the latter, we believe that CHI-S can be implemented safely in Uganda. Our reflections are presented here to promote feedback and discussion

Peste des Petits Ruminants at the Wildlife–Livestock Interface in the Northern Albertine Rift and Nile Basin, East Africa

In the recent past, peste des petits ruminants (PPR) emerged in East Africa causing outbreaks in small livestock across different countries, with evidences of spillover to wildlife. In order to understand better PPR at the wildlife–livestock interface, we investigated patterns of peste des petits ruminants virus (PPRV) exposure, disease outbreaks, and viral sequences in the northern Albertine Rift. PPRV antibodies indicated a widespread exposure in apparently healthy wildlife from South Sudan (2013) and Uganda (2015, 2017). African buffaloes and Uganda kobs <1-year-old from Queen Elizabeth National Park (2015) had antibodies against PPRV N-antigen and local serosurvey captured a subsequent spread of PPRV in livestock. Outbreaks with PPR-like syndrome in sheep and goats were recorded around the Greater Virunga Landscape in Kasese (2016), Kisoro and Kabale (2017) from western Uganda, and in North Kivu (2017) from eastern Democratic Republic of the Congo (DRC). This landscape would not be considered typical for PPR persistence as it is a mixed forest–savannah ecosystem with mostly sedentary livestock. PPRV sequences from DRC (2017) were identical to strains from Burundi (2018) and confirmed a transboundary spread of PPRV. Our results indicate an epidemiological linkage between epizootic cycles in livestock and exposure in wildlife, denoting the importance of PPR surveillance on wild artiodactyls for both conservation and eradication programs

Establishing a single-sex controlled human Schistosoma mansoni infection model for Uganda: protocol for safety and dose-finding trial

Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits

Analysis of the MUII-plus mentorship programme: reflections of Fellows’ experiences and lessons for other programmes

Background: The MUII mentorship programme began 11 years ago with a successful group mentorship model. Over the years, the programme has evolved and is presently anchored on the “GROW” approach. This model allows individuals to: set Goals (What I want?); Reflect (Where am I now?); think of Options (What can I do?); What to implement (my actions?). It is intended to help fellows (current, honorary, alumni) herein referred to as mentees achieve their short, medium, and long-term research, career and professional goals. Methods: A mixed methods study combining a cross-sectional survey, one focus group discussion and 11 in-depth key informant interviews were carried out between November 2018 and January 2019 to 1) assess the status of the mentorship programme, 2) perform a strength weakness opportunity and threats (SWOT) analysis, and 3) identify factors relevant for sustainability. Results: An open invitation was made to 52 fellows to participate in the survey, and 23 responded. Among respondents, the largest proportions were male [70% (16/23)], and PhD fellows [35% (8/23)]. The respondents rated the fellowship experience as excellent [65% (15/23)], and most [78% (18/23)] revealed they had benefitted greatly from the programme. The SWOT analysis revealed outstanding strengths of having regular fellows’ meetings for peer support, and availability of international collaborations, linkages and exposure. Opportunities identified included large pool of mentees within MUII-plus and evidence of fellows taking up leadership positions. The biggest threat to the mentorship programme was the busy schedule of mentors. Conclusions: The MUII-plus mentorship programme has strong potential to offer research and career mentorship to its fellows. To promote sustainability of the programme, there is a need for innovative ways to engage mentors; such as digital platforms (e-mentorship) for greater mentor-mentee interactions.</ns3:p

Analysis of the MUII-plus mentorship programme: reflections of Fellows� experiences and lessons for other programmes

Background: The MUII mentorship programme began 11 years ago with a successful group mentorship model. Over the years, the programme has evolved and is presently anchored on the �GROW� approach. This model allows individuals to: set Goals (What I want?); Reflect (Where am I now?); think of Options (What can I do?); What to implement (my actions?). It is intended to help fellows (current, honorary, alumni) herein referred to as mentees achieve their short, medium, and long-term research, career and professional goals. Methods: A mixed methods study combining a cross-sectional survey, one focus group discussion and 11 in-depth key informant interviews were carried out between November 2018 and January 2019 to 1) assess the status of the mentorship programme, 2) perform a strength weakness opportunity and threats (SWOT) analysis, and 3) identify factors relevant for sustainability. Results: An open invitation was made to 52 fellows to participate in the survey, and 23 responded. Among respondents, the largest proportions were male [70% (16/23)], and PhD fellows [35% (8/23)]. The respondents rated the fellowship experience as excellent [65% (15/23)], and most [78% (18/23)] revealed they had benefitted greatly from the programme. The SWOT analysis revealed outstanding strengths of having regular fellows� meetings for peer support, and availability of international collaborations, linkages and exposure. Opportunities identified included large pool of mentees within MUII-plus and evidence of fellows taking up leadership positions. The biggest threat to the mentorship programme was the busy schedule of mentors. Conclusions: The MUII-plus mentorship programme has strong potential to offer research and career mentorship to its fellows. To promote sustainability of the programme, there is a need for innovative ways to engage mentors; such as digital platforms (e-mentorship) for greater mentor-mentee interactions.</ns3:p

The Evolutionary Dynamics of the Lion Panthera leo Revealed by Host and Viral Population Genomics

The lion Panthera leo is one of the world's most charismatic carnivores and is one of Africa's key predators. Here, we used a large dataset from 357 lions comprehending 1.13 megabases of sequence data and genotypes from 22 microsatellite loci to characterize its recent evolutionary history. Patterns of molecular genetic variation in multiple maternal (mtDNA), paternal (Y-chromosome), and biparental nuclear (nDNA) genetic markers were compared with patterns of sequence and subtype variation of the lion feline immunodeficiency virus (FIVPle), a lentivirus analogous to human immunodeficiency virus (HIV). In spite of the ability of lions to disperse long distances, patterns of lion genetic diversity suggest substantial population subdivision (mtDNA ΦST = 0.92; nDNA FST = 0.18), and reduced gene flow, which, along with large differences in sero-prevalence of six distinct FIVPle subtypes among lion populations, refute the hypothesis that African lions consist of a single panmictic population. Our results suggest that extant lion populations derive from several Pleistocene refugia in East and Southern Africa (∼324,000–169,000 years ago), which expanded during the Late Pleistocene (∼100,000 years ago) into Central and North Africa and into Asia. During the Pleistocene/Holocene transition (∼14,000–7,000 years), another expansion occurred from southern refugia northwards towards East Africa, causing population interbreeding. In particular, lion and FIVPle variation affirms that the large, well-studied lion population occupying the greater Serengeti Ecosystem is derived from three distinct populations that admixed recently

Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022

HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting